A healthy liver contains a minimal amount of fat. When a significant number (usually more than 5%) of the cells in the liver have abnormal fat accumulation the liver is considered diseased. Fatty liver diseases consist of two main categories based on whether they are caused by excessive alcohol consumption or not. Fatty liver diseases that are not caused by excessive alcohol consumption are termed nonalcoholic fatty liver diseases (“NAFLDs”), which consist of simple nonalcoholic fatty liver (“NAFL”) and in a significant portion of subjects proceeds to a more severe form associated with inflammation, called nonalcoholic steatohepatitis (“NASH”). NAFL and/or NASH may also include scarring of the liver known as liver fibrosis or in a more severe form, liver cirrhosis. Scarring of the liver reduces liver function up to and including liver failure.
NAFLDs have many non-mutually exclusive causes including malnutrition, overeating, obesity, diabetes, medications and hyperlipidemia. However, the main cause of NAFLDs appears to be high-fat, high-calorie diets leading to an excess amount of energy which exceeds the storage capacity of adipose tissue and thus is stored in the liver. NASH is positively correlated with the metabolic syndrome (i.e. diseases related to diabetes mellitus type 2, such as insulin resistance, trunk obesity, hyperlipidemia and hypertension) although the correlation is not 100%.
Over the past 20 years, the number of cases of NAFLDs has nearly doubled. Almost 30% of people in developed countries are estimated to have NAFL or NASH including 20% of adults in the United States. The best method of prevention and treatment of NAFLDs include a low-calorie diet and exercise. However, due to voluntary non-compliance, an inability to exercise and/or long term diet restriction, many patients must also be treated with pharmaceuticals.
Current pharmaceutical treatments that have been proposed or tested in prior trials, although not yet approved for NAFLDs include vitamin C, vitamin E, betaine, metformin, orlistat, selenium, thiazolidinediones (“TZDs”), urodeoxycholic acid, and pentoxifilline. Ongoing FDA-approved trials include: GR-MD-02, a galactose-containing polysaccharide manufactured by Galectin Therapeutics Inc., for the treatment of NASH with attendant liver fibrosis; a Hadassah, LTD drug technology, which includes feeding patients with natural antibodies to intestinal flora associated with NAFLDs; and obeticholic acid for treatment of NASH with attendant liver fibrosis being conducted by Intercept Pharmaceuticals, Inc.
A diverse array of other agents have been proposed as either direct or indirect treatments for NAFLDs (e.g.: interleukin-22 (U.S. Patent Application Publication No. 20140377222); piperine derivatives (U.S. Patent Application Publication No. 20140371271); nuclear transport modifiers (U.S. Patent Application Publication No. 20140336113) and Bifidobacterium pseudocatenulatum strain CECT 7765 (U.S. Patent Application Publication No. 20140369965).
Lipodystrophic syndromes present with either a complete or partial lack of adipose tissue. Although less prevalent than NAFLDs, lipodystrophic syndromes have a more severe presentation. Patients with generalized lipodystrophy (i.e. congenital and/or acquired) have metabolic abnormalities consistent with the metabolic syndrome and hepatomegaly due to fatty infiltration of the liver. Patients with congenital partial lipodystrophy also present with metabolic complications including insulin resistance, usually accompanied by hypertriglyceridemia, hyperlipidemia and possibly hyperglycemia.
The treatment plan for lipodystrophic syndrome is similar to that for NAFLDs including diet, exercise and treatment of underlying metabolic disturbances. Many of the same drugs used to treat NAFLDs have been implemented to treat lipodystrophic syndromes. A recently approved medication for treating congenital complete generalized lipodystrophy associated with metabolic dysfunction is leptin.
Despite the attention that NAFLDs and lipodystrophic syndromes have recently received there is still no effective pharmaceutical options for their treatment. The lack of an effective treatment combined with the rapid rise in prevalence of the diseases creates an immediate need in the art for new drugs and methods of treatment for NAFLDs and/or lipodystrophic syndromes.